Carboxylated naphthalene formaldehyde condensation polymers as dental plaque barriers

ABSTRACT

Polymers useful in compositions and methods for preventing the attachment of dental plaque to the surface of the teeth of mammals comprise alkali metal salts of certain carboxylated naphthalene formaldehyde polymers in a pharmaceutically acceptable vehicle and the periodic application thereof to teeth.

TECHNICAL FIELD

This invention relates to certain carboxylated aromatic polymericcompounds, to oral hygiene compositions comprising these polymericcompounds, and to methods using such compositions to prevent attachmentof bacteria to teeth. More particularly, it relates to certaincarboxylated polymeric materials that have been found useful ininhibiting the agglutination of oral microbes on teeth.

BACKGROUND ART

The prevention of the deposition of dental plaque on teeth is a highlydesired result. Dental plaque results when cariogenic bacteria aggregatein colonies on the surface of teeth and form a tenacious depositthereon. The presence of plaque on teeth is believed to be a precursorto development of gingivitis, dental caries and periodontal disease.

While many attempts have been made to control the effects of cariogenicbacteria and the dental plaque they produce, for example, fluoride,flossing, brushing, etc., treatments, these are typically directed toeither counteracting the secondary effects of plaque on the teeth andgums, or to the removal of plaque that is already formed on and adheringto the teeth and surrounding tissue. Such treatments are not, however,entirely successful, and must be supplemented with periodic treatment bydental professionals. To date, there is no commercially feasible hometreatment method for preventing the formation of plaque or its adhesionto teeth.

The Invention

Certain hydrophilic carboxylic acid and carboxylic acid salt derivativesof certain naphthalene formaldehyde condensation polymers have beensynthesized. The salts of these polymers inhibit the deposition ofdental plaque onto human teeth. These hydrophilic polymeric carboxylatesare substantially soluble in water or water/organic solvent vehicles,have good film forming characteristics and, accordingly, are applied toteeth from various dentifrice formulations, mouth rinses, or other oralhygiene procedures. While the mechanism of action of the hydrophilicpolymeric films in retarding plaque deposition is not known withabsolute certainty, it is presumed that the films of anionically-chargedpolymers deposited on teeth effect a mutual repulsion between thenegatively charged polymer film and the negatively chargedmicroorganisms in oral fluids responsible for plaque generation. Thecarboxylated polymers of this invention are especially effective ascomponents of dentifrices and other oral hygiene preparations inreducing dental plaque deposition on teeth.

The hydrophilic, polymeric carboxylates found useful for dental plaquecontrol in accordance with the present invention are essentiallycarboxylic acid salt derivatives of formaldehyde condensation polymersof certain naphthalene compounds wherein the repeating unit of thepolymer has the structure (A), ##STR1## wherein R is selected from thegroup consisting of --COOM and --CH₂ COOM (including mixtures of thesetwo substituents), and M is selected from the group consisting oflithium, sodium and potassium. The free acids (wherein M is hydrogen),while too insoluble in aqueous media to be useful as barrier agents inthe compositions of this invention, are new compositions of matter thatare readily converted to the above salts by methods well known to thoseskilled in the art and are, therefore, considered to be within the scopeof this invention as useful precursors of the salts used as barrieragents in the compositions and method of this invention.

The formaldehyde polymers of this invention are preferably prepared bythe acid catalyzed condensation of aqueous 37% formaldehyde orparaformaldehyde with naphthoic acid and/or naphthylacetic acid understandard conditions reported in the literature for other compounds andreviewed extensively in the text by J. F. Walker, "Formaldehyde", R. E.Krieger Publishing Co., Third Edition, 1975. The resultant polymers,having repeating units of structure (A), wherein M is hydrogen, areconverted to their alkali metal salts by neutralization or ion-exchangereactions.

Typical naphthalene compounds which can be utilized for preparation ofthe formaldehyde polymers of this invention are 1-naphthoic acid,2-naphthoic acid, 1-naphthylacetic acid, and 2-naphthylacetic acid. Theexact position for orientation of the methylene (--CH₂ --) linkages onthe aromatic rings is not known and is generally recognized as beingcomplex and varied. It is well understood that some of the formaldehydelinkages may not be solely of the --CH₂ type but can also involve someextended units, such as CH₂ OCH₂ and CH₂ (OCH₂)_(n) OCH₂, or otherpossibilities (cf. Walker, supra). However, despite these uncertainties,NMR data on the carboxylated formaldehyde polymers of this inventionindicate that the formaldehyde linkages consists essentially of themethylene linkage depicted in structure (A).

The formaldehyde polymers are prepared by heating approximatelyequimolar quantities of formaldehyde and the selected naphthalenecompounds in an inert solvent, in the presence of an acid catalyst suchas sulfuric acid, p-toluenesulfonic acid, methanesulfonic acid, orperchloric acid, for several hours. Depending on the nature of theformaldehyde polymer, the latter precipitates from the reaction mixtureeither directly on cooling to room temperature or upon quenching inwater. The preferred solvent for the reaction is acetic acid, a solventknown to favor formation of polymers having oxygen-free linkages(Walker, supra, p. 439), such as those of the present invention.

The alkali metal salts of the carboxylated polymers of this inventionare conveniently prepared by neutralization of a water or alcoholsolution of the polymeric carboxylic acid derivative with alkali metalhydroxide solutions to the potentiometric endpoint. The salts arerecovered by filtration, solvent stripping, or freeze drying, dependingon the type of solvent used and whether the salt precipitates directlyfrom the solvent media. Alternatively, carboxylic acid salts can beprepared by addition of at least stoichiometric quantities of an alkalimetal oxide, carbonate, acetate, chloride, nitrate, or sulfate to thecarboxylic acid polymer. The salts either precipitate directly and arecollected, or they are isolated after solvent stripping. Purification ofthe carboxylate salt by dialysis is the preferred procedure for the morehighly water soluble salts.

For testing the carboxylated naphthalene formaldehyde polymers of thisinvention, the in vitro test procedure we have employed beging withgrowth of plaque in small jars containing sterilized trypticase mediathat has been supplemented with sucrose. Typically, ten jars areindividually inoculated with 0.5 ml of unpooled freshly collected humanplaque from 10 subjects. In a control series, a presterilized glassslide or an extracted human tooth is inserted into each jar. In the testseries, the tooth or glass slide is pretreated with a 1% solution of thetest compound (dissolved in water or other vehicle), allowed to dry inorder to deposit a thin film of the compound on the surface, and theglass slide or tooth placed in the growth media. The jars are incubatedunder anaerobic conditions for two days at 37° C. The tooth or glassslide is removed, air dried, and stained with 0.15% FD&C #3 red dyesolution to reveal the accumulated plaque deposits. The tooth or glassslide is scored for plaque density on a 0 to 5 scale. Plaque barrieractivity is reported as the % of average plaque reduction, as comparedto appropriate controls for ten subjects.

The alkali metal salts of the formaldehyde polymers of naphthoic andnaphthylacetic acids of this invention are highly effective in reducingthe deposition of plaque when tested by this in vitro test procedure.For example, the sodium salts of the formaldehyde polymers of1-naphthoic acid and 1-naphthylacetic acid showed plaque reductions of33% and 57%, respectively.

The formaldehyde polymers of this invention have a molecular weight ofabout 500 to about 10,000, preferably about 2,000 to 5,000. They aresubstantially soluble in water or mixed solvents comprising water and anorganic solvent miscible therewith (generally at least 1% w/w).

EXAMPLE 1 Sodium Salt of 1-Naphthoic Acid/Formaldehyde Polymer

A solution of 17.2 g (0.100 mole) 1-naphthoic acid and 8.1 g (0.100mole) 37% formaldehyde in 85 ml. glacial acetic acid was stirred andmaintained at a temperature of 90°-110° C. during addition of 5.6 ml.(0.100 mole) 96% sulfuric acid over 10 minutes. The solution wasmaintained at 110° C. for another 24 hours, during which time thesolution became progressively darker in color and some solids appeared.On cooling to 50° C., heavy precipitation of white solids occurred.Addition of 150 ml. water produced a heavier deposition of solids whichwas filtered, washed with water, and dried. The solids were slurried inboiling toluene, filtered hot, and dried to afford 11.1 g of the1-naphthoic acid/formaldehyde polymer showing a softening point of about220° C.

A solution of 1.8068 g of the 1-naphthoic acid polymer in 40 ml.methanol was neutralized from pH 2.5 to pH 8.0 with 16.6 ml. 0.512 N.methanolic sodium hydroxide. The neutraliziation equivalent value was212.6. Removal of the solvent from the neutralizaed solution gave 1.9 gof the sodium salt of the polymer which was soluble in water andmethanol.

EXAMPLE 2 Sodium Salt of 1-Naphthylacetic Acid/Formaldehyde Polymer

Into a flask was charged 18.6 g (0.100 mole) 1-naphthylacetic acid, 93ml. glacial acetic acid, and 8.1 g (0.100 mole ) 37% formaldehyde. Withstirring, 5.6 ml. (0.100 mole) 96% sulfuric acid was added and themixture heated at a gentle reflux (110° C.) for about 21 hours. Oncooling to room temperature and dilution with 200 ml. water, heavydeposition of solids took place. The polymeric solids were filtered,washed with water, re-slurried in 200 ml. boiling water, and filteredhot. The moist solids were dried in vacuo at 60° C. to give 17.3 g ofthe 1-naphthylacetic acid/formaldehyde polymer, a tan colored powder.

A solution of 2.0251 g of the polymer was prepared in a mixture of 40ml. acetone and 40 ml. tetrahydrofuran and neutralized to pH 7.7 with20.6 ml 0.512 N methanolic sodium hydroxide solution. The sodium salt ofthe polymer precipitated and was filtered, washed with acetone, anddried. The neutralization equivalent value was 192 and in good agreementwith the theoretical value of 198 for a 1:1 naphthylaceticacid/formaldehyde condensation polymer.

EXAMPLE 3 Sodium Salt of 2-Naphthoic Acid/Formaldehyde Polymer

Using the same procedure as described in Example 1, 2-naphthoic acid and37% formaldehyde are reacted to afford the 2-naphthoic acid/formaldehydepolymer, which is then neutralized with sodium hydroxide to give thewater soluble, polymeric sodium salt.

EXAMPLE 4 Potassium Salt of 2-Naphthylacetic Acid/Formaldehyde Polymer

In a manner similar to that described in Example 2, 2-naphthylaceticacid is converted to the corresponding formaldehyde polymer of structure(A), which, after neutralization with methanolic potassium hydroxide,affords the potassium salt.

The plaque barrier oral compositions of this invention may comprise anyconventional pharmaceutically acceptable oral hygiene formulation thatcontains (and is compatible with) an effective amount of a plaquebarrier agent as defined herein. Such formulations include, for example,mouthwashes, rinses, irrigating solutions, abrasive and nonabrasive geldentifrices, denture cleansers, coated dental floss and interdentalstimulator coatings, chewing gums, lozenges, breath fresheners, foamsand sprays.

The plaque barrier agents may be present in these formulations ineffective concentrations generally in the range of from about 0.05weight percent to as much as 30 weight percent or the limit ofcompatibility with the vehicle. However, no advantage will be derivedfrom concentrations in excess of about 20 weight percent. A preferredconcentration range for the plaque barrier agents in the formulations ofthe invention is from about 0.5 to about 10 weight percent. A morepreferred range is from about 2 to about 8 percent by weight, about 5%being the presently most preferred concentration in a nonabrasive gelvehicle.

The pH of these plaque barrier preparations should be between pH 5.0 and10.0, preferably between pH 5.0 and 8.0, more preferably between aboutpH 6.0 and 7.5. Lower pH than 5.0 is undesirable because of the possibleenhancement of enamel demineralization.

Suitable conventional pharmaceutically acceptable vehicles that can beemployed with the plaque barrier agents to prepare the barriercompositions of this invention may comprise water, ethanol; suchhumectants as polypropylene glycol, glycerol and sorbitol; such gellingagents as cellulose derivatives, for example, Methocel,carboxymethylcellulose (CMC 7MF) and Klucel HF,polyoxypropylene/polyoxyethylene block copolymers, for example, PluronicF-127, Pluronic F-108, Pluronic P-103, Pluronic P-104, Pluronic P-105,and Pluronic P-123, colloidial magnesium aluminosilicate complexes suchas Veegum, and mucoprotein thickening agents such as Carbopol 934; gelstabilizers such as the silicon dioxides, for example, Cab-O-Sil M5, andpolyvinylpyrrolidione; sweeteners such as sodium saccharin;preservatives such as citric acid, sodium benzoate, cetylpyridiniumchloride, potassium sorbate, methyl and ethyl parabens; detergents suchas sodium lauryl sulfate, sodium cocomonoglyceride sulfonate, sodiumlauryl sarcosinate and polyoxyethylene isohexadecyl ether (Arlasolve200) and approved colors and flavors.

The following specific examples will serve further to illustrate theplaque barrier compositions of this invention.

EXAMPLE A--Mouthwash Solution

    ______________________________________                                        Barrier Agent         0.5-2.0 % w/w                                           Glycerol (humectant)  6.0                                                     Pluronic F-108        1.0                                                     Sodium saccharin (sweetener)                                                                        0.3                                                     Deionized Water       q.s.                                                    Flavors               1.0                                                                           100.0                                                   ______________________________________                                    

EXAMPLE B--Mouthwash Solution

    ______________________________________                                        Plaque Barrier Agent  0.5-3.0 % w/w                                           Ethanol, USP          15.0                                                    Pluronic F-108 (foaming agent)                                                                      2.0                                                     Glycerol (humectant)  10.0                                                    Sorbitol (humectant)  10.0                                                    Sodium saccharin (sweetener)                                                                        0.2                                                     Deionized Water       q.s.                                                    Flavors               0.2                                                                           100.0                                                   ______________________________________                                         EXAMPLE C--Abrasive Dentrifice Gel

    ______________________________________                                        Plaque Barrier Agent   2.0-10.0                                                                              % w/w                                          Fumed Silica (abrasive)                                                                              55.0                                                   Sodium Lauryl Sulfate (detergent)                                                                    1.5                                                    Glycerol (humectant)   10.0                                                   Carboxymethylcellulose (gelling agent)                                                               2.0                                                    Sodium saccharin (sweetener)                                                                         0.2                                                    Sorbitol (humectant)   10.0                                                   Flavors                1.0                                                    Deionized Water        q.s.                                                   Preservative           0.05                                                                          100.0                                                  ______________________________________                                    

EXAMPLE D--Chewing Gum

    ______________________________________                                        Plaque Barrier Agent                                                                              1.0-11.0 % w/w                                            Gum Base            21.3                                                      Sugar               48.5-58.5                                                 Corn Syrup (Baume 45)                                                                             18.2                                                      Flavors             1.0                                                                           100.0                                                     ______________________________________                                    

EXAMPLE E--Nonabrasive Gel Dentifrice

    ______________________________________                                        Plaque Barrier Agent 0.05-30.0                                                                              % w/w                                           Sorbistat (preservative)                                                                           0.15                                                     Deionized Water      q.s.                                                     Silicon Dioxide (gel stabilizer)                                                                   1.0                                                      Pluronic F-127 (gelling agent)                                                                     20.0                                                     Sodium Saccharin     0.2                                                      Flavors              1.5                                                                           100.0                                                    ______________________________________                                    

EXAMPLE F

The following formulation illustrates a presently preferred nonabrasivegel composition containing a barrier agent in accordance with thepresent invention.

    ______________________________________                                        Ingredients           % w/w                                                   ______________________________________                                        Distilled Water       q.s.                                                    Sodium Saccharin (sweetener)                                                                        0.20                                                    Sodium Benzoate (preservative)                                                                      0.30                                                    FD & C Blue #1 (0.1% aq. soln.)                                                                     0.27                                                    D & C Yellow #10 (0.5% aq. soln.)                                                                   0.50                                                    Gelling agent         18.00                                                   Glycerol (Humectant)  20.00                                                   Cab-O-Sil M5 (Silicon Dioxide)                                                                      1.00                                                    Plaque Barrier Agent  5.00    (dry basis)                                     Flavor                0.80                                                                          100.0                                                   ______________________________________                                    

While the details of preparing all of the above formulations are wellwithin the skill of the art, a suggested procedure for preparing the gelformulation of this example will be described for completeness.

In a first container the water, sodium saccharin, sodium benzoate anddyes are mixed. Then the container is put into an ice bath. When thetemperature reaches 6° C., the gelling agent is added and the contentsmixed slowly until the gelling agent is dissolved. Then the solution isheated to 70° C.

Into a second container is added the glycerin. Then the Cab-O-Sil M5 issprinkled in with mixing. Then the plaque barrier agent is added andmixing continued to a smooth paste. The paste is then heated in a waterbath with mixing to a temperature of 70° C.

The contents of the first container are added to the second containerand blended together until the batch is homogenous while maintaining a70° C. temperature. Then the flavoring is added, all mixing is stopped,and the formulation allowed to settle for approximately one hour. Ifnecessary to remove air bubbles, overnight refrigeration may beemployed.

These compositions are preferably employed from one to three times dailyin a routine oral hygiene program to prevent the attachment of plaque tothe teeth.

Variations can, of course, be made without departing from the spirit orscope of the invention.

I claim:
 1. An oral hygiene composition comprising an effective amountfor preventing deposition of dental plaque on teeth of a condensationpolymer of formaldehyde with a naphthalene compound selected from thegroup consisting of 1-napthoic acid, 2-naphthoic acid, 1-naphthylaceticacid and 2-naphthylacetic acid, said polymer having repeating units ofstructure (A), ##STR2## wherein R is selected from the group consistingof --COOM and --CH₂ COOM, n is such that the molecular weight of saidpolymer is from about 500 to about 10,000, and M is selected from thegroup consisting of lithium, sodium, and potassium, in apharmaceutically acceptable oral hygiene vehicle compatible with saidpolymer.
 2. A method of preventing deposition of dental plaque on teethcomprising periodically applying to the teeth a composition of claim 1.3. The method of claim 2 wherein said composition is applied from about1 to about 3 times per day.
 4. The composition of claim 1 in the form ofan oral hygiene formulation selected from the group consisting ofmouthwashes, mouthrinses, irrigating solutions, abrasive geldentifrices, non-abrasive gel dentifrices, denture cleansers, coateddental floss, coated interdental stimulators, chewing gums, lozenges,breath fresheners, foams and sprays.